Du Qiong, Zhu Bin, Zhai Qing, Yu Bo
Department of Pharmacy, Shanghai Cancer Center, Fudan UniversityShanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China.
Am J Transl Res. 2017 Jul 15;9(7):3360-3373. eCollection 2017.
Doxorubicin (Dox) is an anthracycline antibiotic widely used in cancer treatment. Although its antitumor efficacy appears to be dose dependent, its clinical use is greatly restricted by development of cardiotoxicity. Sirtuin-3 (Sirt3) is the major deacetylase within the mitochondrial matrix that plays an important role in regulation of cardiac function. This study was performed to identify the regulatory role of Sirt3 on Dox-induced cardiac hypertrophy and mitochondrial dysfunction in rats in vivo and in vitro. We found that adenovirus-mediated overexpression of Sirt3 resulted in marked inhibition of Dox-induced cardiac hypertrophy, particularly mitochondrial dysfunction including opening of the mitochondrial permeability transition pore (mPTP), loss of mitochondrial membrane potential (ΔΨm), respiration dysfunction, and mitochondrial reactive oxygen species (ROS) production. Further study revealed that Bcl-2-like 19 kDa-interacting protein 3 (Bnip3) mRNA and protein expression levels were altered in cardiomyocytes in vivo and in vitro after Dox treatment, and these increases were significantly inhibited by Sirt3 overexpression. Interestingly, the Dox-disrupted mitochondrial Cox1-Ucp3 complexes were preserved by Sirt3 overexpression. Finally, recombinant adeno-associated virus-mediated overexpression of Bnip3 (AAV-Bnip3) in rat hearts and cardiomyocytes completely impaired the protective effects of Sirt3 on Dox-induced cardiac toxicity and mitochondrial dysfunction. These findings reveal a new molecular mechanism in which Sirt3 restores mitochondrial respiratory chain defects, and cell viability of Dox-damaged cardiomyocytes is mutually dependent on and obligatorily linked to suppression of Bnip3 gene expression. Interventions that antagonize Bnip3 may contribute to the beneficial effect of Sirt3 regarding prevention of mitochondrial injury and heart failure in cancer patients undergoing chemotherapy.
阿霉素（Dox）是一种广泛应用于癌症治疗的蒽环类抗生素。尽管其抗肿瘤疗效似乎具有剂量依赖性，但其临床应用因心脏毒性的发生而受到极大限制。沉默调节蛋白3（Sirt3）是线粒体基质中的主要去乙酰化酶，在心脏功能调节中起重要作用。本研究旨在确定Sirt3在体内外对阿霉素诱导的大鼠心脏肥大和线粒体功能障碍的调节作用。我们发现，腺病毒介导的Sirt3过表达显著抑制了阿霉素诱导的心脏肥大，尤其是线粒体功能障碍，包括线粒体通透性转换孔（mPTP）开放、线粒体膜电位（ΔΨm）丧失、呼吸功能障碍和线粒体活性氧（ROS）生成。进一步研究表明，阿霉素处理后体内外心肌细胞中Bcl-2样19 kDa相互作用蛋白3（Bnip3）的mRNA和蛋白表达水平发生改变，而Sirt3过表达可显著抑制这些增加。有趣的是，Sirt3过表达可保留阿霉素破坏的线粒体Cox1-Ucp3复合物。最后，重组腺相关病毒介导的Bnip3（AAV-Bnip3）在大鼠心脏和心肌细胞中的过表达完全削弱了Sirt3对阿霉素诱导的心脏毒性和线粒体功能障碍的保护作用。这些发现揭示了一种新的分子机制，即Sirt3恢复线粒体呼吸链缺陷，阿霉素损伤的心肌细胞的细胞活力与Bnip3基因表达的抑制相互依赖并紧密相连。拮抗Bnip3的干预措施可能有助于Sirt3在预防接受化疗的癌症患者线粒体损伤和心力衰竭方面发挥有益作用。
